Table 3.

MicroRNAs described for their role in electrical remodelling

miRNA in AF		Target(s) in AF		Experimental Model	Function	Reporting studiesa
miR-31	↑	nNOS, dystrophine [52]	↓	51 AF, 165 SR patients, human cardiac myocytes, goat ATP model	Upregulation in AF correlated with decreased nNOS and unchanged Dystrophine mRNA levels. In vitro inhibition restored nNOS protein and normalized APD in myocytes from AF patients. MiR-31 directly targets both dystrophin and nNOS, and negatively reduce the respective protein by promoting nNOS mRNA decay and inhibiting the translation of dystrophin mRNA.	[30, 52–54]
miR-21	↑	CACNA1C, CACNB2 [59]	↓	10 permAF, 10 SR patients, atrial cadiomyocytes, HL-1 cells	An upregulationin AF was seen along with a decrease in CACNA1C, CACNB2 mRNA and ICaL in human atrial cardiomyocytes. Its overexpression in vitro decreased ICaL density and Cav1.2 protein levels. This miR directly targeted CACNA1C and CACNB2.	[40, 44, 46, 53, 56, 59, 74]
miR-208a/b	↑	CACNA1C, CACNB2 [58]	↓	16 permAF, 15 SR patients, sheep ATP, human cardiac myocytes, HL-1 cells	Upregulation of miR-208b, but not of miR-208a in AF patients compared to controls correlated with decreased mRNA, protein levels and ICaL density. Overexpression of both miR208a/b in vitro reduced Cav1.2 protein levels. MiR-208a/b directly targeted CACNA1C and CACNB2.	[31, 53, 58, 62, 71, 74, 111, 114]
miR-328	↑	CACNA1C, CACNB1 [45]	↓	12 AF, 10 SR patients, canine ATP model, mice burst pacing, miR-328 TG mice, miR-328 sponge TG mice, in vivo forced expression in canines, neonatal rat cardiomyocytes	Upregulation in AF correlated with decreased human and canine mRNA and Cav1.2, Cavβ1 protein levels. In vivo overexpression of this miR promoted AF vulnerability, decreased APD, Cav1.2, Cavβ1 and ICaLdensity. Inhibition dampened AF vulnerability. MiR-328 directly targeted CACN1C and CACNB1.	[30, 37–39, 45, 56, 57]
miR-1	↑	KCNE1, KCNB2 [63]	↓	Rabbit ATP model, in vivo forced expression and inhibition in rabbits	ATP was associated with increased miR-1 decreased KCNE1 and KCNB2 mRNA and protein levels, shortening of AERP and an increase in IKs and AF susceptibility. MiR-1 in vivo overexpression further enhanced these effects, while inhibition with antimiR-1 alleviated these results. MiR-1 directly targeted KCNE1 and KCNB2.	[15, 46, 63, 74, 135]
	↓	KCNJ2 [15]	↑	31 AF, 31 SR patients, in vitro TP of human atrial slices	Downregulation in tissue of AF patients correlated with increased mRNA, Kir2.1 levels and IK1 density. TP of human atrial slices induced a miR-1 decrease and Kir2.1 increase.
mir-26a/b	↓	KCNJ2 [16, 68]	↑	12 AF, 10 SR patients, canine A/VTP model, mice A/VTP model, in vivo forced expression in mice, canine and mice fibroblasts, TG and KO mice, H9c2 cells	Downregulation of miR-26b and miR-26a in particular in AF patients or AF animal models correlated with an upregulation of mRNA, Kir2.1 levels and IK1 density. Both in vivo and in vitro inhibition of miR-26 increased IK1 and AF vulnerability, whereas overexpression of dampened AF vulnerability. MiR-26 directly targeted KCNJ2.	[16, 46, 68–70, 86]
miR-30d	↑	KCNJ3 [71]	↓	14 AF, 19 SR patients, neonatal rat cardiomyocytes	Upregulation in cardiomyocytes from AF patients correlated with decreased mRNA and Kir3.1 levels. MiR-30d overexpression in vitro decreased KCNJ3, Kir3.1 and IKACh, while inhibition had the opposite effects. MiR-30d directly targeted KCNJ3.	[46, 71]
miR-499	↑	KCNN3 [74]	↓	4 permAF, 4 SR, HL-1 cells	Upregulation in tissue of AF patients correlated with decreased SK3 protein. MiR-499 in vitro overexpression suppressed KCNN3 levels and SK3 levels while inhibition enhanced SK3. MiR-499 directly targeted KCNN3.	[45, 53, 58, 71, 74]

^aStudies reporting about the specific miRNA in AF. These include both explorative and functional studies in tissue and plasma and may present conflicting data regarding upregulation or downregulation of the miRNA

Abbreviations: AF atrial fibrillation, APD action potential duration, ATP atrial tachypacing, cav1.2 L-type voltage-dependent calcium channel subunit α1C, Cavβ1 L-type voltage-dependent calcium channel subunit β1, I _Ca,L, L-type voltage-dependent calcium channel current, KO knockout, LA left atrium, MVS mitral valve stenosis, ox-LDL oxidized low-density lipoprotein, permAF permanent/chronic AF, RA right atrium, SR sinus rhythm/controls, AERP atrial effective refractory period, AF atrial fibrillation, ATP atrial tachypacing, I _K1 inward rectifier K⁺ current, I _KACh acetylcholine regulated inward rectifier potassium current, IKs potassium currents, Kir2.1 inward rectifier potassium channel 2, Kir3.1 acetylcholine regulated inward rectifier potassium channel 3, LA left atrium, permAF permanent/chronic AF, RA right atrium, SR sinus rhythm/controls, SK3 small conductance calcium-activated potassium channel 3, TG transgenic, TP tachypacing, VTP ventricular tachypacing